Table 1.
Summary of various trials of JAK inhibitors, IL-23, IL-12/23 and IL-36 inhibitors.
| Drug | Study/year | Setting/Dose | Number of patients | Response | Adverse effects | Conclusion | Phase |
|---|---|---|---|---|---|---|---|
| JAK inhibitors Tofacitinib | Papp et al. (87)/ 2012 | Psoriasis vulgaris–Tofacitinib 2 mg twice daily vs. 5 mg twice daily vs. 15 mg twice daily vs. placebo | Tofacitinib 2 mg-49; 5 mg−49; 15 mg−49; placebo-50 | At week 12, higher proportion of patients achieved PASI 75 in all tofacitinib groups: 25·0% (2 mg), 40·8% (5 mg) and 66·7% (15 mg) compared with placebo (2·0%). | Infections and infestations | Oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis. | Phase 2b |
| Bisonette et al. (13)/ 2015 | Moderate-to-severe plaque psoriasis–tofacitinib 5 mg or 10 mg twice daily for 24 weeks. The patients achieving both PASI75 and Physician's Global Assessment of “clear” or “almost clear” received a placebo or the previous dose. At relapse (>50% reduction in the PASI improvement during initial treatment) or week 40, the patients received the initial dose. |
Tofacitinib 5 mg−331; 10 mg−335 | 33·5% and 55·2% achieved both PASI 75 and PGA responses in tofacitinib 5 and 10 mg twice daily group, respectively. | Elevations in low-density lipoprotein–cholesterol levels | Patients who received continuous treatment maintained a response more effectively than placebo. Patients who relapsed, 60% reattained a response with tofacitinib. |
Phase 3 | |
| Bachelez et al. (88) / 2015 | Moderate-to-severe plaque psoriasis–Tofacitinib 5 mg twice daily vs. 10 mg twice daily vs. Etanercept 50 mg twice weekly vs. placebo | Tofacitinib 5 mg−330; 10 mg−332; Etanercept- 336; placebo- 108 | At week 12, PASI75–39·5% in tofacitinib 5 mg group, 63·6% in tofacitinib 10 mg group, 58·8% in the etanercept group, and 5·6% in the placebo group. | Serious adverse events−2% in tofacitinib 5 mg group, 2% in tofacitinib 10 mg group, 2% in etanercept group, and 2% in placebo group. | Tofacitinib 10 mg twice daily was Non-inferior to etanercept and was superior to placebo, but 5 mg twice daily did not show Non-inferiority to etanercept. | Phase 3, randomized, multicentre, placebo-controlled, 12-week, Non-inferiority trial. | |
| Papp et al. (12)/ 2015 | Plaque psoriasis–tofacitinib 10 or 5 mg or placebo, twice daily. | Tofacitinib 5 mg−745; 10 mg−741; placebo- 373 | At week 16, a greater proportion of patients achieved PGA responses with tofacitinib 5 and 10 mg twice daily vs. placebo. | Similar across groups. Twelve patients reported herpes zoster across the tofacitinib treatment groups. | Oral tofacitinib demonstrated significantly high efficacy as compared to placebo, during 16 weeks of treatment. | Phase 3 | |
| Mease et al. (15)/ 2017 | Psoriatic arthritis–tofacitinib 5-mg twice daily, 10-mg twice daily, adalimumab 40-mg once every 2 weeks, placebo with a blinded switch to 5-mg tofacitinib at 3 months, or placebo with a blinded switch to 10-mg tofacitinib at 3 months. | Tofacitinib 5 mg−107; 10 mg−104; adalimumab- 106; placebo- 52 (5 mg switch), 53 (10 mg switch). | ACR20 response rates at month 3 were 50% in 5-mg tofacitinib group and 61% in 10-mg tofacitinib group, 33% in placebo group, 52% in the adalimumab group. | The rate of adverse events was 66% in 5-mg tofacitinib group, 71% in 10-mg tofacitinib group, 72% in adalimumab group. | Efficacy of tofacitinib was superior to placebo at month 3 in patients who previously had an inadequate response to conventional synthetic DMARDs. | 12-month, double-blind, active-controlled and placebo-controlled, phase 3 trial | |
| Gladman et al. (16)/ 2017 | Psoriatic arthritis–tofacitinib 5 mg twice daily; 10 mg twice daily; placebo, with a switch to 5 mg tofacitinib twice daily at 3 months; or placebo, with a switch to 10 mg tofacitinib twice daily at 3 months. | Tofacitinib 5 mg−132; 10 mg−132; placebo- 66 (5 mg switch), 65 (10 mg switch). | ACR20 response- 50% with 5-mg tofacitinib and 47% with 10-mg dose, as compared to 24% with placebo. | 4 serious infections, 3 herpes zoster infections, 1 myocardial infarction, and 1 ischemic stroke. | Tofacitinib was more effective than placebo over 3 months in reducing disease activity. | 6-month randomized, placebo-controlled, double-blind, phase 3 trial | |
| Baricitinib | Papp et al. (19)/ 2016 | Moderate-to-severe psoriasis- placebo or oral baricitinib at 2, 4, 8 or 10 mg once daily for 12 weeks. | baricitinib 2 mg- 32, 4 mg- 72, 8 mg- 64, 10 mg- 69, Placebo- 34 | At week 12, patients in 8-mg (43%) and 10- mg (54%) baricitinib groups achieved PASI-75 than in placebo group (17%). Statistically significant PASI-90 responses were achieved in 8-mg and 10-mg groups at 8 and 12 weeks. |
treatment-emergent AE rates were 44, 50, 47, 58 and 64% for placebo and 2-, 4-, 8- and 10-mg baricitinib groups. | Treatment with baricitinib for 12 weeks achieved significant improvements in PASI-75. | Phase 2b, randomized, double-blind, placebo-controlled, dose-ranging study. |
| IL-12/23 inhibitors Ustekinumab |
Phoenix-I (89)/ 2008 | Moderate-to-severe psoriasis- Ustekinumab 45 mg or 90 mg at weeks 0, 4 and then every 12 weeks; or placebo at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. | Placebo-255; 45 mg- 255; 90 mg- 256 | 67·1% patients receiving ustekinumab 45 mg, 66·4% receiving ustekinumab 90 mg, and 3·1% receiving placebo achieved PASI 75 at week 12. | Adverse events occurred in 54·5% in ustekinumab and 48·2% in placebo group. | Ustekinumab seems to be efficacious for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least a year in most patients. | Phase 3, parallel, double-blind, placebo-controlled study. |
| Phoenix-II (90)/ 2008 | Moderate-to-severe psoriasis- Ustekinumab 45 mg or 90 mg at weeks 0, 4 and then every 12 weeks; or placebo. Partial responders (patients achieving ≥50% but <75% improvement from baseline in PASI) were re-randomized at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks. |
Placebo- 410; 45 mg- 409; 90 mg−411 | 66·7% patients receiving ustekinumab 45 mg, 75·7% receiving ustekinumab 90 mg, and 3·7% receiving placebo achieved 75% improvement in PASI at week 12. More partial responders who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than those who received the same dose every 12 weeks. |
Serious adverse events were seen in 2% patients in 45 mg group, 1·2% in 90 mg group, and 2% in placebo group. | Ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis. Intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen. | Multicentre, phase 3, double-blind, placebo-controlled study. | |
| Griffiths et al. (91)/ 2010 | Moderate-to-severe psoriasis- 45 or 90 mg of ustekinumab (at weeks 0 and 4) or high-dose etanercept (50 mg twice weekly for 12 weeks) | 45 mg−209; 90 mg−347; etanercept−347 | 75% improvement in the PASI at week 12 in 67.5% of patients receiving 45 mg of ustekinumab and 73.8% of patients receiving 90 mg, as compared with 56.8% of those with etanercept. | One or more adverse events occurred in 66% of patients in 45 mg ustekinumab and 69.2% in 90 mg ustekinumab and in 70% in etanercept group. | Efficacy of ustekinumab 45 or 90 mg was superior to high-dose etanercept over a 12-week period. | Randomized, multicentre study. | |
| PSUMMIT I (35) | Active psoriatic arthritis−45 mg ustekinumab, 90 mg ustekinumab, or placebo at week 0, week 4, and every 12 weeks thereafter. | Placebo- 206; 45 mg- 205; 90 mg−204 | More ustekinumab-treated [42·4%] in the 45 mg group and [49·5%] in the 90 mg group than placebo-treated [22·8%] patients achieved ACR20 at week 24. | Adverse events were similar in the ustekinumab [41·8%] and placebo groups [42·0%]. | Ustekinumab significantly improved active psoriatic arthritis. | Phase 3, multicentre, double-blind, placebo-controlled trial | |
| PSUMMIT II (36) | Active Psoriatic Arthritis- ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. | Placebo- 104; 45 mg- 103; 90 mg- 105 | More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24; all benefits were sustained through week 52. | No unexpected adverse events were observed. | Ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in Psoriatic arthritis. | phase 3, multicentre, placebo-controlled trial | |
| IL-23 inhibitor Guselkumab |
VOYAGE-I (92) | Moderate to severe plaque psoriasis- guselkumab 100 mg (weeks 0 and 4, then every 8 weeks); placebo/guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20, then every 8 weeks); or adalimumab (80 mg week 0, 40 mg week 1, then 40 mg every 2 weeks through week 47). | Placebo- 174; 100 mg−329; adalimumab−334 | Guselkumab was superior to placebo at week 16 (73.3 vs. 2.9% [PASI-90]). Guselkumab was also superior to adalimumab for PASI 90 at week 16 (73.3 vs. 49.7%), week 24 (80.2 vs. 53.0%), and week 48 (76.3 vs. 47.9%). | The proportions of patients with adverse events were similar in the guselkumab and adalimumab group. | Guselkumab demonstrated superior efficacy compared with adalimumab. | phase 3, randomized, double-blind, placebo- and active comparator-controlled trial |
| VOYAGE-II (93) | Moderate to severe plaque psoriasis- Similar to VOYAGE I; at week 28, guselkumab PASI90 responders were rerandomized to guselkumab or placebo with guselkumab after loss of response. Placebo → guselkumab responders and adalimumab responders received placebo, then guselkumab after loss of response. | Placebo- 248; 100 mg−496; adalimumab−248 | Guselkumab was superior to adalimumab and placebo at week 16. From weeks 28 to 48, better persistence of response was observed in guselkumab maintenance vs. withdrawal groups. Of adalimumab Non-responders who switched to guselkumab, 66.1% achieved PASI 90 at week 48. | Adverse events were comparable among groups. | Guselkumab is highly effective maintenance therapy, including in adalimumab Non-responders. | phase 3, double-blind, placebo- and active comparator–controlled | |
| DISCOVER I (37) | Active psoriatic arthritis | Placebo- 126; 100 mg every 4 weeks- 128; 100 mg at 0 and 4 weeks, then every 8 weeks- 127 | Significantly greater proportions of patients receiving guselkumab every 4-week (59·4%) and every 8-week (52·0%) vs. placebo (22·2%) achieved ACR20 at week 24. | Serious adverse events occurred in none of patients in guselkumab every 4-week, 3·1% in guselkumab every 8-week, and 4·0% in placebo group. | Guselkumab demonstrated a favorable benefit-risk profile and is an effective treatment option in patients with active psoriatic arthritis. | Phase-3, double-blind, placebo-controlled study | |
| Tildrakizumab | reSURFACE I (94) | Moderate-to-severe chronic plaque psoriasis- Tildrakizumab at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomized from placebo to tildrakizumab. | Placebo- 154 100 mg- 309 200 mg-308 | At week 12, 62% in 200 mg group and 64% in 100 mg group achieved PASI 75, compared with 6% in placebo group. | Nasopharyngitis. | Tildrakizumab 200 mg and 100 mg were efficacious compared with placebo. | Parallel group, double-blind, randomized controlled study |
| reSURFACE II (94) | Moderate-to-severe chronic plaque psoriasis- Tildrakizumab at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomized from placebo to tildrakizumab; etanercept was given twice weekly in part 1 and once weekly during part 2). | Placebo- 156 100 mg- 307 200 mg-314 Etanercept−313 | At week 12, 66% in 200 mg group, and 61% in 100 mg group achieved PASI 75, compared with 6% in placebo group and 48% in the etanercept group. | The incidence of severe infections, malignancies, and major adverse cardiovascular events were low and similar across treatment groups. | Tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated. | Parallel group, double-blind, randomized controlled study | |
| Risankizumab | UltIMMa-1 and UltIMMa-2 (95) | Moderate-to-severe chronic plaque psoriasis−150 mg risankizumab, 45 mg or 90 mg ustekinumab or placebo. Following 16-week double-blind treatment period (part A), patients initially assigned to placebo switched to 150 mg risankizumab at week 16; other patients continued their originally randomized treatment (part B, double-blind, weeks 16–52). Study drug was administered subcutaneously at weeks 0 and 4 during part A and at weeks 16, 28, and 40 during part B. | UltIMMa-1 - Placebo- 102; 150 mg−304; ustekinumab−100 UltIMMa-2- Placebo-98; 150 mg−294; Ustekinumab- 99 | At week 16 of UltIMMa-1, PASI 90 was achieved by 75·3% patients receiving risankizumab vs. 4·9% receiving placebo and 42·0% receiving ustekinumab. At week 16 of UltIMMa-2, PASI 90 was achieved by 74·8% patients receiving risankizumab vs. 2·0% receiving placebo and 47·5%. |
The frequency of treatment-emergent adverse events in UltIMMa-1 and UltIMMa-2 was similar across risankizumab, placebo, ustekinumab, and placebo to risankizumab groups. | Risankizumab showed superior efficacy to both placebo and ustekinumab. | Phase 3, randomized, double-blind, placebo-controlled and active comparator-controlled trials |
| IL-36 inhibitor Spesolimab |
Bachelez et al. (96) | Generalized Pustular Psoriasis- single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups received an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. | Spesolimab 900 mg- 35; placebo- 18 | At week 1, 54% in the spesolimab group had a pustulation sub-score of 0, as compared with 6% in the placebo group. | Drug reactions−2 patients. (drug-induced hepatic injury- 1); infections−17% through the first week; antidrug antibodies−46%. | Spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. | Phase 2 randomized trial |